WO2023086521A1 - Inhibiteurs de btk - Google Patents

Inhibiteurs de btk Download PDF

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Publication number
WO2023086521A1
WO2023086521A1 PCT/US2022/049618 US2022049618W WO2023086521A1 WO 2023086521 A1 WO2023086521 A1 WO 2023086521A1 US 2022049618 W US2022049618 W US 2022049618W WO 2023086521 A1 WO2023086521 A1 WO 2023086521A1
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methyl
alkyl
membered monocyclic
pharmaceutically acceptable
compound
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PCT/US2022/049618
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English (en)
Inventor
Brian T. Hopkins
Bin Ma
Jürgen Schulz
Marta Nevalainen
TeYu CHEN
Robin Prince
Harold George Vandeveer
Isaac Marx
Simone SCIABOLA
Zain YOUSAF
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Biogen Ma Inc.
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Publication of WO2023086521A1 publication Critical patent/WO2023086521A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • BTK INHIBITORS RELATED APPLICATION This application claims the benefit of the filing date, under 35 U.S.C. ⁇ 119(e), of U.S. Provisional Application No. 63/277,879, filed on November 10, 2021, the entire contents of which are incorporated herein by reference.
  • TECHNICAL FIELD Provided are certain agents that inhibit Bruton’s tyrosine kinase (Btk), and methods of making and using such agents.
  • BACKGROUND Protein kinases are a large multigene family consisting of more than 500 proteins which play a critical role in the development and treatment of a number of human diseases in oncology, neurology and immunology.
  • the Tec kinases are non-receptor tyrosine kinases which consists of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk) and Bmx (bone -marrow tyrosine kinase gene on chromosome X; also known as Etk)) and are primarily expressed in haematopoietic cells, although expression of Bmx and Tec has been detected in endothelial and liver cells.
  • Tec tyrosine kinase expressed in hepatocellular carcinoma
  • Btk Brun's tyrosine kinase
  • Itk interleukin-2 (IL-2)-in
  • Tec kinases (Itk, Rlk and Tec) are expressed in T cell and are all activated downstream of the T- cell receptor (TCR).
  • Btk is a downstream mediator of B cell receptor (BCR) signaling which is involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
  • PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, which then induces additional B- cell signaling.
  • IP3 inositol triphosphate
  • DAG diacylglycerol
  • Mutations that disable Btk enzymatic activity result in XLA syndrome (X- linked agammaglobulinemia), a primary immunodeficiency.
  • Tec kinases are targets of interest for autoimmune disorders.
  • One aspect of the disclosure is a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: X 0 is N, X 1 is C, X 2 is N, X 4 is N and X 5 is CH; X 0 is CR 0 , X 1 is C, X 2 is N, X 4 is N and X 5 is CH; X 0 is CR 0 , X 1 is N, X 2 is C, X 4 is N and X 5 is CH; X 0 is CR 0 , X 1 is N, X 2 is C, X 4 is CH and X 5 is CH; X 0 is CR 0 , X 1 is C, X 2 is N, X 4 is CH and X 5 is CH; X 0 is CR 0 , X 1 is C, X 2 is N, X 4 is CH and X 5 is CH; or X 0 is CH, X 1 is N, X X
  • the present disclosure provides a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods of treating a disorder responsive to inhibition of Btk in a subject. The methods comprise administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Btk.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in treating a disorder responsive to inhibition of Btk.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl comprises 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, an alkyl comprises from 6 to 20 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.
  • Alkenyl refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon double bond. In some embodiments, alkenyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms or 2-6 carbon atoms. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds, or more.
  • alkenyl groups include ethenyl, n-propenyl, iso-propenyl, n-but-2-enyl, n-hex-3-enyl and the like.
  • Alkynyl refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon triple bond. In some embodiments, alkynyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms or 2-6 carbon atoms can be preferred. The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, or more.
  • alkynyl groups examples include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.
  • alkoxy refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a --O-- C 1-4 alkyl group wherein C 1-4 alkyl is as defined herein).
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like.
  • alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.
  • aryl is defined to include all-carbon monocyclic or fused- ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • An aryl group may have 6, 8, 9 or 10 carbon atoms in the ring(s).
  • an aryl group may have 6 or 10 carbon atoms in the ring(s).
  • (C6-C10)aryl aromatic radicals containing from 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl and the like.
  • An aryl group having 6 carbon atoms in the ring(s) may be optionally substituted by 1 to 5 suitable substituents.
  • the number of carbon atoms in a group is specified herein by the prefix “C x-xx ” or “C x -C xx ”, wherein x and xx are integers.
  • C 1-4 alkyl is an alkyl group which has from 1 to 4 carbon atoms.
  • the term “carbocyclyl”, “carbocycle” or “carbocyclic ring” refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged or spiro ring systems) ring system which has from 4- to 12-ring members, all of which are carbon.
  • the term “carbocyclyl” encompasses cycloalkyl groups and cycloalkenyl groups.
  • the carbocyclyl is a 3- to 7-membered monocyclic carbocyclyl.
  • Exemplary 3- to 7-membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl and cycloheptatrienyl.
  • the carbocyclyl is a 7- to 10-membered bicyclic carbocyclyl.
  • Exemplary 7- to 10-membered bicyclic carbocyclyls include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo [3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1] nonanyl, bicyclo[3.3.2]decanyl, decalinyl, naphthyl and indanyl.
  • a fused bicyclic carbocyclyl has a 4 to 7 membered carbocycyl fused to a 3 to 7 membered non-aromatic carbocyclyl. Examples include decahydronapthalene, octahydro-1H- indene, octahydropentalene, decahydroazulene, decahydro-1H-annulene, bicycle[4.2.0]octane, bicycle[3.2.0]heptane and the like.
  • a bridged bicyclic carbocyclyl comprises a non-aromatic 5 to 7 membered carbocyclyl which shares three ring atoms with a 5 to 7 membered non-aromatic carbocyclyl.
  • bridged bicyclics carbocycles include bicyclo[2.2.1]hepantyl, bicyclo[3.2.1]octanyl, and bicyclo [3.3.1]nonanyl.
  • Cycloalkyl refers to completely saturated monocyclic hydrocarbon groups of 3-7 carbon atoms, including cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl and cyclopentyl; and “cycloalkyenyl” refers to unsaturated non-aromatic monocyclic hydrocarbon groups of 3-7 carbon atoms, including cyclpenteneyl, cyclohexenyl and cyclopentenyl.
  • cycloalkyl includes completely saturated monocyclic or bicyclic or spiro hydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms. In some embodiments, cycloalkyl is a 3- to 6-membered monocyclic cycloalkyl. “Halogen” or “halo” may be fluoro, chloro, bromo or iodo. The term “haloalkyl” or "halo-substituted alkyl” or refers to an alkyl group having at least one halogen substitution.
  • Haloalkoxy is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF 2 or –OCF 3 .
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
  • Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like.
  • a heteroaryl is a 5-membered heteroaryl.
  • a 5-membered heteroaryl include, but are not limited to, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged or spiro ring systems) ring system which has from 3- to 12-ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
  • C can be oxidized
  • N can be oxidized (e.g., N(O)) or quaternized
  • S can be optionally oxidized to sulfoxide and sulfone.
  • the heterocyclyl is a 4- to 6-membered or 3- to 7-membered monocyclic heteterocyclyl. In some embodiments, the heterocyclyl is a 7- to 10-membered bicyclic heterocyclyl, which can be fused, bridged or spiro bicyclic heterocyclyl. In some embodiments, the bicyclic heterocyclyl may include a non-aromatic heterocycle fused to a heteroaromatic ring.
  • Examples of monocyclic heterocyclyl include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.
  • a “fused ring system” has from 8 to 12 members (ring atoms) and two rings which share two adjacent ring atoms.
  • a fused bicyclic heterocyclyl has a 4 to 7 membered heterocycyl fused to a 4 to 7 membered heterocycyl or a 3 to 7 membered carbocyclyl.
  • a fused bicyclic heterocyclyl can also have a 4 to 7 membered heterocycyl fused to a 5 to 6 membered heteroaryl.
  • Examples include cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycheptaazapanyl, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloazapanyl, furanopyrrolidinyl, furanopiperidinyl, furanoazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, dihydropyrrolo[3,4-d]thiazoyl and the like.
  • a “bridged bicyclic ring system” (also referred to herein as a “bridged bicyclic” or “bridged ring system”) has 7 to 10 members (ring atoms) and two rings which share three adjacent ring atoms.
  • a bridged bicyclic heterocyclyl comprises a 5 to 7 membered heterocycyl which shares three ring atoms with a 5 to 7 membered heterocycyl or a 5 to 7 membered carbocyclyl.
  • Examples nitrogen containing bridged bicyclics include azabicyclo[2.2.1]hepantyl, azabicyclo[3.2.1]octanyl, azabicyclo [3.3.1]nonanyl, diazabicyclo[2.2.1]hepantyl, diazabicyclo[3.2.1]octanyl and diazabicyclo [3.3.1]nonanyl.
  • oxygen containing bridged bicyclics examples include oxobicyclo[2.2.1]hepantyl, oxobicyclo[3.2.1]octanyl, oxobicyclo [3.3.1]nonanyl, oxa-azabicyclo[2.2.1]hepantyl, oxa- azabicyclo[3.2.1]octanyl and oxa-azabicyclo[3.3.1]nonanyl.
  • a “spiro ring system” (also referred to herein as a “spirocycle”) has 8 to 12 members (ring atoms) and two rings which share one ring atom.
  • a spirobicyclic heterocyclyl comprises a 4 to 7 membered heterocycyl which shares one atom with a 4 to 7 membered heterocycyl or a 4 to 7 membered non-aromatic carbocyclyl.
  • 8 to 12 nitrogen containing spiro rings systems include 3,4-azabicyclooctanyl, 4,4-azabicyclononanyl, 3,5-azabicyclononanyl, 3,6-azabicyclodecanyl, 4,5-azabicyclodecanyl, 3,7-azabicycloundecanyl, 4,6- azabicycloundecanyl and 5,5-azabicycloundecanyl.
  • Examples of 8-12 oxygen containing spiro ring systems include 3,4-oxobicyclooctanyl, 4,4-oxobicyclononanyl, 3,5- oxobicyclononanyl, 3,6-oxobicyclodecanyl, 4,5-oxobicyclodecanyl, 3,7- oxobicycloundecanyl, 4,6-oxobicycloundecanyl and 5,5-xobicycloundecanyl.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, or ⁇ -glycerophosphate.
  • Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts.
  • Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalken
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group.
  • Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso- propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like.
  • carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.
  • the compounds or pharmaceutically acceptable salts thereof as described herein, can contain one or more asymmetric centers in the molecule.
  • any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture).
  • stereochemical purity means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.
  • stereochemical purity means the weight percent of the desired enantiomer relative to the combined weight of all stereoisomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included.
  • stereoisomeric purity of the named or depicted stereoisomers is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%.
  • the stereoisomeric purity the weight percent of the desired stereoisomers encompassed by the name or structure relative to the combined weight of all of the stereoisomers.
  • the name or structure encompasses one stereoisomer in pure or substantially pure form, as well as mixtures thereof (such as mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s)).
  • the disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.
  • the invention provides deuterated compounds disclosed herein, in which any or more positions occupied by hydrogen can include enrichment by deuterium above the natural abundance of deuterium.
  • one or more hydrogen atoms are replaced with deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • hydrogen is present at all positions at its natural abundance.
  • the compounds or pharmaceutically acceptable salts thereof as described herein, may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated.
  • II. COMPOUNDS OF THE DISCLOSURE In a first embodiment, the compound of the invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.
  • X 3 is -OR 5 , -N(R 5 ) 2 , 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclyl, wherein the 5- to 6-membered heteroaryl and the 4- to 7-membered monocyclic heterocyclyl are optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5 or 6) R 50 , and the remaining variables are as described in the first embodiment.
  • R 0 is H; and the remaining variables are as described in the first or second embodiment.
  • R 0 is H; and the remaining variables are as described in the first or second embodiment.
  • the compound is represented by the following formula: , ,
  • X 3 is -OR 5 , -N(R 5 )2, 5- membered heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 5- membered heteroaryl and the 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one to three R 50 ; and R 5 is C 1-6 alkyl optionally substituted with C 1-6 alkoxy; and the remaining variables are as described in the first, second, third or fourth embodiment.
  • X 3 is selected from phenyl, azetidine, morpholine, oxadiazole, piperazine, pyrazole, tetrazole, each optionally substituted with one or two R 50 ; and the remaining variables are as described in the first, second, third, fourth or fifth embodiment.
  • X 3 is selected from: , and m is 0, 1 or 2; and the remaining variables are as described in the first, second, third, fourth or fifth embodiment.
  • X 3 is selected from -O- CH 2 - CH 2 -OCH 3 , -N(CH 3 )2, wherein represents a bond to Ring B; and the remaining variables are as described in the first, second, third, fourth or fifth embodiment.
  • R 50 for each occurrence is independently C 1-6 alkyl or a 4- to 6-membered monocyclic heterocyclyl, wherein the C1- 6alkyl represented by R 50 is optionally substituted with halo or CN; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.
  • R 50 for compounds of formula (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salts thereof, R 50 , for each occurrence, is independently selected from –CH 3 , -CH 2 -CN and ; and the remaining variables are as described in the ninth embodiment.
  • R 50 for compounds of formula (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salts thereof, R 50 is –CH 3 ; and the remaining variables are as described in the ninth embodiment.
  • Ring A is phenyl, 5 or 6- membered heteroaryl or 5 to 10-membered monocyclic or bicyclic heterocyclyl, each or which is optionally substituted with one to three R 4 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.
  • Ring A is selected from 3-azabicyclo[3.2.1]octane, azepane, phenyl, piperidine, pyridine and pyrrolidine, each of which is optionally substituted with one to three R 4 ; and the remaining variables are as described in the twelfth embodiment.
  • A is selected from: , wherein represents a bond to Ring B, and ⁇ represents bond to and the remaining variables are as described in the twelfth embodiment.
  • n is 0, 1, 2; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment.
  • Ring A is selected from:
  • R 4 is selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment.
  • R 4 is selected from Cl, F, -CH 3 and -CHF2; and the remaining variables are as described in the seventeenth embodiment.
  • R 1 is 5- membered heteroaryl optionally substituted with one or two R 10 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.
  • R 1 is selected from oxazole, oxadiazole, pyrazole, tetrazole and triazole, each of which is optionally substituted with one or two R 10 ; and the remaining variables are as described in the nineteenth embodiment.
  • R 1 is selected from: the remaining variables are as described in the nineteenth embodiment.
  • R 10 for each occurrence, is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, each of which is optionally substituted with one to three R 15 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiment.
  • R 10 for each occurrence, is independently selected from C 1-4 alkyl and cyclopropyl, each of which is optionally substituted with one or three R 15 ; and the remaining variables are as described in the twenty-second embodiment.
  • R 15 for each occurrence, is independently selected from halogen, C 1-4 alkyl and C 1-4 haloalkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment.
  • R 15 for each occurrence, is independently selected from F, –CH 3 and -CH 2 F; and the remaining variables are as described in the twenty-fourth embodiment.
  • R 10 for each occurrence, is independently selected from –C(CH 3 ) 3 , -C(CH 3 ) 2 -CH 2 F, , variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiment.
  • R 2 is H; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.
  • R 1 and R 2 together with their intervening atoms, form a Ring D selected from 5- to 7-membered monocyclic heterocyclyl and 7- to 10-membered bicyclic heterocyclyl, wherein Ring D is optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5 or 6) R 100 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.
  • Ring D is selected from piperazinone and dihydropyrrolo[3,4-d]thiazolone, wherein Ring D is optionally substituted with one or two R 100 ; and the remaining variables are as described in the twenty-eighth embodiment.
  • Ring D is selected from: , wherein represents a bond to –C(R 3 )–Ring A; and the remaining variables are as described in the twenty-eighth embodiment.
  • R 100 for each occurrence, is independently selected from C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl, each of which is optionally substituted with one or two R 150 ; and R 150 , for each occurrence, is independently selected from C 3-6 cycloalkyl and 4- to 6-membered monocyclic heterocyclyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty- third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment.
  • R 100 for each occurrence, is independently selected from C 1-6 alkyl and oxetanyl, wherein the C 1-6 alkyl represented by R 100 is optionally substituted with R 150 ; and R 150 , for each occurrence, is independently selected from cyclobutyl and oxetanyl; and the remaining variables are as described in the thirty-first embodiment.
  • R 100 for each occurrence, is independently selected from –CH 3 , -CH 2 -CH 2 -CH 3 , -CH(CH 3 )2, -C(CH 3 )3, - CH 2 -CH(CH 3 ) 2 , -CH 2 -C(CH 3 ) 3 , ; and the remaining variables are as described in the thirty-first embodiment.
  • R 3 is selected from H and C 1-6 alkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty- eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment.
  • R 3 is H or -CH 3 ; and the remaining variables are as described in the thirty-fourth embodiment.
  • R 3 and R 4 together with their intervening atoms, form a Ring E, wherein Ring E is selected from 4- to 7-membered monocyclic carbocycle and 4- to 7-membered monocyclic heterocycle, wherein Ring E is optionally substituted with R 300 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty- eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment.
  • Ring E is 5- to 7- membered monocyclic heterocycle optionally substituted with R 300 ; and the remaining variables are as described in the thirty-sixth embodiment.
  • Ring E is represented by the following structural formula: , wherein represents a point of fusion to Ring A and rep 2 resents a bond to –N(R )- C(O)-R 1 ; and the remaining variables are as described in the thirty-sixth embodiment.
  • R 300 for each occurrence, is independently selected from C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl represented by R 300 are each optionally substituted with one to three R 350 ; and R 350 , for each occurrence, is independently halogen; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty- eighth, twenty-ninth, thirtieth, thirty-first, thirty-second
  • R 300 for each occurrence, is independently selected from –CH 2 -CF 3 and ; and the remaining variables are as described in the thirty-ninth embodiment.
  • the compound is represented by the following formula: o , or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5-membered heteroaryl optionally substituted with R 10 ; R 10 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl optionally substituted with C 1-3 alkyl; X 3 is a 5-membered heteroaryl or a 6-membered monocyclic saturated heterocyclyl, each of which is optionally substituted with R 50 ; R 50 is C 1-3 alkyl or C 1-3 haloalkyl; Ring A is phenyl, 6-membered heteroaryl or 6-membered monocyclic saturated heteorcyclyl; R 4 , for each occurrence, is independently selected from halogen, C 1-3 alkyl and C 1-3 haloalkyl; and n is 0, 1 or 2.
  • R 1 is selected from oxadiazole, triazole and tetrazole, each of which is optionally substituted with R 10 ;
  • X 3 is pyrozole or piperazine, each of which is optionally substituted with R 50 ; and
  • Ring A is phenyl, pyridine or piperidine; and the remaining variables are as described in the forty-first embodiment.
  • R 1 is selected from:
  • X 3 is selected from: wherein ⁇ represents a bond to Ring B, and ⁇ represents bond to and the remaining variables are as described in the forty-first embodiment.
  • ring A is selected from: , wherein represents a bond to Ring B, and ⁇ represents bond t remaining variables are as described in the forty-third embodiment.
  • R 10 is –C(CH 3 ) 3 or ;
  • R 4 for each occurrence, is independently selected from F, -CH 3 and -CHF 2 ; and R 50 is –CH 3 ; and the remaining variables are as described in the forty-first, forty-second, forty-third or forty-fourth embodiment.
  • the invention also includes both the neutral form and pharmaceutically acceptable salts of the compounds disclosed in the exemplification (e.g., compounds of Examples 1- 174). III.
  • Another embodiment is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the activity of Btk, or to otherwise affect the properties and/or behavior of Btk, e.g., stability, phosphorylation, kinase activity, interactions with other proteins, etc.
  • the present invention provides methods of decreasing Btk enzymatic activity. In some embodiments, such methods include contacting a Btk with an effective amount of a Btk inhibitor.
  • the present invention further provides methods of inhibiting Btk enzymatic activity by contacting a Btk with a Btk inhibitor of the present invention.
  • One embodiment of the invention includes a method of treating a disorder responsive to inhibition of Btk in a subject comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods of treating autoimmune disorders, inflammatory disorders, and cancers in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis.
  • ADAM acute disseminated
  • inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.
  • PID pelvic inflammatory disease
  • IBD inflammatory bowel disease
  • reperfusion injury rheumatoid arthritis
  • transplant rejection e.g., and vasculitis
  • vasculitis e.g., rheumatoid arthritis or lupus.
  • the present invention provides a method of treating multiple sclerosis.
  • cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g.
  • lymphoma e.g., anaplastic large-cell lymphoma
  • leukemia e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia
  • multiple myeloma malignant mesothelioma, malignant melanoma
  • colon cancer e.g. microsatellite instability-high colorectal cancer.
  • the present invention provides a method of treating leukemia or lymphoma.
  • the term “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • the term “treating” or ‘treatment” refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • the effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 ⁇ g -500 mg.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal comprises any suitable delivery method.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a compound or pharmaceutically acceptable salt thereof as described herein may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the compound or pharmaceutically acceptable salt thereof as described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like.
  • Such compositions and preparations should contain at least about 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions can be such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the compounds or pharmaceutically acceptable salts thereof as described herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Useful dosages of a compound or pharmaceutically acceptable salt thereof as described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949, which is incorporated by reference in its entirety.
  • the amount of a compound or pharmaceutically acceptable salt thereof as described herein, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.
  • the a compound or pharmaceutically acceptable salt thereof as described herein can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.
  • the disclosed method can include a kit comprising a compound or pharmaceutically acceptable salt thereof as described herein and instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject.
  • kits that are known to those skilled in the art, such as a kit comprising a (such as sterile) solvent for dissolving or suspending a compound or pharmaceutically acceptable salt thereof as described herein or composition prior to administering a compound or pharmaceutically acceptable salt thereof as described herein or composition to a cell or a subject.
  • the subject can be a human.
  • the invention is illustrated by the following examples, which are not intended to be limiting. IV. EXEMPLIFICATIONS A.
  • Abbreviations and Acronyms include the following: ABPR: automated back pressure regulator; Ac2O: acetic anhydride; ACN: acetonitrile; Aq.: aqueous; Ar : argon; Bn: benzyl; Boc: tert-butoxy carbonyl; Boc 2 O: di-tert-butyl decarbonate; BPin: pinacolatoboron; (BPin)2 or B2pin2: bis(pinacolato)diboron, i.e., 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi- 1,3,2-dioxaborolane; br: broad; t-BuOH: tert butanol; n-BuLi: n-butyl lithium; °C: degrees Celsius; CHCl 3 : chloroform; CDCl 3 : deutero-chloroform; CDI: 1,1
  • PG is a suitable N protecting group, typically a carbamate and preferable tert-butyl carbamate.
  • LG is a leaving group, typically a halide, mesylate or triflate and preferably Br, Cl or triflate.
  • the compound of Formula (IV’) may be prepared from the compounds of Formulae (II’) and (III’) by process step a) a palladium catalysed, cross-coupling reaction, such as a Suzuki reaction.
  • Typical cross-coupling reaction conditions comprise a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in a suitable aqueous solvent at between RT and the reflux temperature of the reaction.
  • Preferred conditions comprise, reaction of the compounds of Formulae (II’) and (III’), in the presence of tBuXPhos PdG3, Pd(t-Bu3P)2, Pd(dppf)Cl 2 , or RuPhos in combination with Pd 2 (dba) 3 and a suitable base such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , K 3 PO 4 or KF in a suitable solvent such as aqueous dioxane at between 40°C and 100°C.
  • the compound of Formula (V’) may be prepared from the compound of Formula (IV’) according to process step b) de-protection of a N protecting group, under acidic conditions.
  • Preferred conditions comprise, reaction of the compound of Formula (IV’) with HCl or TFA in a suitable solvent such as MeOH, dioxane, EtOAc or DCM at between RT and 50°C.
  • a suitable solvent such as MeOH, dioxane, EtOAc or DCM
  • the compound of Formula (I) may be prepared according to process step c) an amide bond formation, from the amine of Formula (V’) and R 1 CO 2 H, in the presence of a suitable coupling agent and organic base, in a suitable polar aprotic solvent.
  • Preferred conditions comprise the reaction of the acid, R 1 CO 2 H with the amine of Formula (V’) in the presence of coupling agent, T3P®, HATU or CDI, in the presence of an organic base such as TEA or DIPEA, in a solvent, such as DMF, EtOAc, dioxane or MeCN at between RT and the reflux temperature of the reaction.
  • the compounds of Formula (I) may be prepared according to process step d), an amide bond formation, by reaction of the amine of Formula (V’) with R 1 CO 2 (C1- C4 alkyl) in the presence of DABAL-Me3, according to the method described by Novak et al. (Tet. Lett.2006, 47, 5767).
  • Preferred conditions comprise reaction of the ester, R 1 CO 2 (C 1 -C 4 alkyl) with the amine of Formula (V’) in the presence of DABAL-Me3, in a suitable solvent such as THF or dioxane at between RT and 45°C.
  • a second process wherein A ring is phenyl or 5 or 6-membered heteroaryl, compounds of Formula (IV’), may be prepared from compounds of Formulae (II’), (VI’) and (VII’) as shown in Scheme 2.
  • Hal is halogen, preferably Cl or Br, and W is a boronic acid or boronate ester.
  • the compound of Formula (VII’) may be obtained from the compounds of Formulae (II’) and (VI’) according to process step (a), a Suzuki reaction, as previously described in Scheme 1.
  • X 3 is 5- to 6-membered heteroaryl
  • the compound of Formula (IV) may be obtained from the compounds of Formula (VII’) and X 3 -W according to process step (a), a Suzuki reaction, as previously described in Scheme 1.
  • the compound of Formula (IV’) may be obtained by process step d) a Buchwald-Hartwig cross- coupling reaction.
  • Typical conditions comprise, reaction of X 3 H with the compound of Formula (VII’) in the presence of a suitable inorganic base, a suitable palladium catalyst in the presence of suitable phosphine ligands, in a suitable solvent at elevated temperature.
  • Preferred conditions comprise, reaction of the compounds of Formulae (VII’) and X 3 H in the presence of RuPhos in combination with Pd2(dba)3, in the presence of a suitable base such as K 2 CO 3 , K 3 PO 4 or Cs 2 CO 3 in a suitable solvent such as dioxane or toluene at between 70°C and 110°C.
  • a suitable base such as K 2 CO 3 , K 3 PO 4 or Cs 2 CO 3
  • a suitable solvent such as dioxane or toluene at between 70°C and 110°C.
  • the compound of Formula (IV’) may be prepared from compounds of Formulae (III’) and (VIII’) as shown in Scheme 3.
  • Scheme 3 The compound of Formula (IV’) may be prepared according to process step e) an amination reaction.
  • Typical conditions comprise reaction of the amine of Formula (VIII’) with the compound of Formula (III’), optionally in the presence of an organic or inorganic base, such as DIPEA or Cs 2 CO 3 in IPA or DMF at RT.
  • an organic or inorganic base such as DIPEA or Cs 2 CO 3 in IPA or DMF at RT.
  • the compound of Formula (I) may be prepared from the compounds of Formulae (II’), (VI’), (X’), (XI’) and (XII’) as shown in Scheme 4.
  • the compound of Formula (II’) may be prepared from the compound of Formula (XI’), according to process step (f), a boronate ester formation achieved by treatment with a suitable boronate such as (BPin)2, in the presence of a suitable inorganic base, such as K 2 CO 3 or KOAc and a suitable catalyst, such as, Pd(dppf)Cl 2 in a suitable non-polar solvent at between RT and elevated temperature.
  • Preferred conditions comprise, treatment of the compound of Formula (II’) with (BPin)2 in the presence of Pd(dppf)Cl 2 in the presence of KOAc in dioxane, at between RT and 90°C.
  • the compound of Formula (X’) may be prepared from the compound of Formula (II’) according to process step b) a deprotection reaction, as previously described in Scheme 1.
  • the compound of Formula (XI’) may be prepared from the compound of Formula (X’) and R 1 CO 2 H according to process step c) or R 1 CO 2 (C 1 -C 4 )alkyl according to process step d) as previously described in Scheme 1.
  • the compound of Formula (XII’) may be prepared from the compounds of Formulae (XI’) and (VI’) according to process step a) as previously described in Scheme 1.
  • the compound of Formula (I) may be prepared from the compound of Formula (XII’) and X 3 H according to process steps a) or e) as previously described.
  • the compounds of Formula (XI’) may be prepared from the compound of Formula (XII’) as shown in Scheme 5.
  • Scheme 5 The compound of Formula (XI’) may be prepared from the compound of Formula (XII’) according to process step f) as previously described in Scheme 4.
  • the compounds of Formula (XI’) may be prepared from the compound of Formula (XII’) as shown in Scheme 6.
  • Scheme 6 wherein the A ring is linked to the B ring through a N atom, the compounds of Formula (XI’) may be prepared from the compound of Formula (XII’) as shown in Scheme 6.
  • the compound of Formula (XV’) may be prepared from the compound of Formula (X’) and R 1 CO 2 H according to process step c) or R 1 CO 2 (C 1 -C 4 )alkyl according to process step d) as previously described in Scheme 1.
  • the compound of Formula (XVI’) may be obtained from the compound of Formula (XVI’) according to process step b) as previously described in Scheme 1.
  • the compound of Formula (I) may be obtained from the compounds of Formulae (III’) and (XVI’) according to process step (e) as previously described in Scheme 3.
  • Compounds of Formulae (I) may be converted to alternative compounds of Formulae (I), by standard chemical transformations such as for example, alkylation of a heteroatom such as N, via reductive amination, or alkylation in the presence of an organic or inorganic base in a suitable solvent such as MeCN, using methods well known to those skilled in the art.
  • the compounds of Formulae (II’), (III’), (VI’), (VIII’), (XI’), (XIII’) and (XIV’) are commercially available, may be prepared by analogy to methods known in the literature, or the methods described in the Experimental section below. It will be appreciated by those skilled in the art that it may be necessary to utilize a suitable protecting group strategy for the preparation of compounds of Formula (I).
  • Typical protecting groups may comprise, carbamate and preferably Boc for the protection of amines. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
  • C. Experimental Preparative HPLC conditions In the Example described below, the following preparative HPLC methods were used.
  • Example 2 Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide
  • 1-(Tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1H-pyrazole-4-carboxamide was obtained as a beige solid (15.7 mg, 42% yield), from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid following a similar method to that described for Example 1, Step 8.
  • Example 3 Synthesis of 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide
  • 2-(tert-Butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-tetrazole-5-carboxamide was obtained as a beige solid (17.7 mg, 47% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and 2-(tert-butyl)-2H-tetrazole-5-carboxylic acid following a similar method to that of
  • Example 4 Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide
  • 1-(tert-Butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a beige solid (18.2 mg, 49% yield), from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and 1-(tert-butyl)-1H-1,2,3- triazole-4-carboxylic acid following
  • Example 5 Synthesis of N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(1- methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid (13.2 mg, 35% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and potassium 5-(1- methylcyclopropyl)-1,2,4-oxadiazole-3-carbox
  • the stock solution (1.2 mL) was added to a vial containing potassium 5-tert-butyl- 1,3,4-oxadiazole-2-carboxylate (25 mg, 121.4 ⁇ mol) which was then cooled to 0 oC. HATU (52 mg) was added, and the reaction stirred overnight at RT.
  • the reaction mixture was diluted with DCM (2 mL) and water (2 mL), the vials shaken, and the layers separated. The aqueous layer was extracted with DCM (2 mL) and the combined organic extracts evaporated.
  • 2-(tert-Butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-tetrazole-5-carboxamide was obtained from 2-tert-butyltetrazole-5-carboxylic acid and (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 6, step 2) following a similar procedure to that described in Example 6, step 3.
  • N-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5- (1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was prepared from (2-fluoro-4-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 6, step 2) and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate using a similar method to that used for Example 6, step 3.
  • Example 9 to 13 The compounds in the following table were prepared from (2-fluoro-4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 6, step 2) and the appropriate carboxylic acid, following a similar procedure to that described in Example 6, step 3.
  • 2-(tert-Butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-tetrazole-5-carboxamide was prepared from 2-tert-butyl-2H-1,2,3,4-tetrazole- 5-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4- yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (Example 14, step 3) following the method used in Example 14, step 4.
  • 1-(tert-Butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1H-pyrazole-4-carboxamide was prepared from 1-tert-butylpyrazole-4-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H- tetrazole-5-carboxamide dihydrochloride (Example 14, step 3) following the method used in Example 14, step 4.
  • 1-(tert-Butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1H-pyrazole-3-carboxamide was prepared from 1-tert-butylpyrazole-3-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H- tetrazole-5-carboxamide dihydrochloride (Example 14, step 3) following the method used in Example 14, step 4.
  • Example 19 Synthesis of 3-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide
  • reaction mixture was cooled to ambient temperature and diluted with water (1 mL), 1M HCl solution (1 mL) and EtOAc (5 mL). The layers were separated, and the aqueous phase was extracted with additional portions of EtOAc. The combined organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Example 20 Synthesis of 5-(1-(fluoromethyl)cyclopropyl)-N-(4-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • 5-(1-(Fluoromethyl)cyclopropyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained (29.6 mg, 47% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and ethyl 5-(1-(fluoromethyl)cyclo
  • Example 21 Synthesis of 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide
  • 2-(tert-Butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-1,2,3-triazole-4-carboxamide was obtained (23.8 mg, 39% yield) from (4-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 1, step 7) and ethyl 2-(tert-butyl)-2H-1,2,3-triazole-4-carboxylate (Journal of
  • Example 22 5-(1-fluoro-2-methylpropan-2-yl)-N-(4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • Example 24 3-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4- oxadiazole-5-carboxamide 3-(tert-Butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4- oxadiazole-5-carboxamide was prepared from 5-tert-butyl-1,2,4-oxadiazole-2-carboxylate and (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride (Example 23, step 3), following the method used in Example 23, step 4.
  • Example 26 to 29 The compounds in the following table were prepared from (4-(6- morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 23, step 3) and the appropriate carboxylic acid, following the method described in Example 25.
  • 1-(2-Methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4- neopentylpiperazin-2-one was obtained (25.1 mg, 40% yield) from 1-(2-methyl-4-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Example 30, step 4) and pivaldehyde following the method described in Example 30, step 5.
  • 1-(2-Methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4- (oxetan-3-ylmethyl)piperazin-2-one was obtained (19.2 mg, 52% yield) from 1-(2-methyl-4- (6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Example 30, step 4) and oxetane-3-carbaldehyde following the method described in Example 30, step 5.
  • Example 33.1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4- neopentylpiperazin-2-one 1. NaH (57.60 mg, 2.40 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1- carboxylate (400 mg, 2.0 mmol) in THF (4.0 mL) at 0°C, the mixture stirred for 1 h, 1- bromo-4-(chloromethyl)benzene (410.96 mg, 2.0 mmol) was added and the reaction stirred at RT for 2 h. The reaction was quenched with aq.
  • 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4- neopentylpiperazin-2-one was obtained (15 mg) from 1-(2-fluoro-4-(6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Example 34, step 4) and pivaldehyde, following a similar method to that used for Example 30, step 5.
  • Example 36 4-isobutyl-3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one 1.
  • Example 37 3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-4-(oxetan-3-yl)piperazin-2-one 3-Methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-4-(oxetan-3-yl)piperazin-2-one was obtained (67.4 mg, 46% yield) from 3-methyl- 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2- one hydrochloride (Example 36, step 5) and oxetan-3-one, following a similar method to that used for Example 30, step 5.
  • Example 39 1-tert-butyl-N-[(5R)-8-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl]-2-(oxetan-3-yl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide 1.
  • Examples 43 to 51 The compounds in the following table were prepared from (4-methyl-1-(6-(1- methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl])-4-piperidyl)methanamine (Example 41, step 2) or (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin- 3-yl)methanamine (Example 42, step 2) and the appropriate carboxylic acid, following a similar method to that used for Example 41, step 3.
  • Example 52 5-(tert-butyl)-N-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide 1.
  • tert-Butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate (160.0 mg, 706.96 ⁇ mol), followed by T3P ® (674.83 mg, 1.06 mmol, 50% purity) were added to a solution of lithium 5- (tert-butyl)-1,2,4-oxadiazole-3-carboxylate (373.49 mg, 2.12 mmol) in DMF (1.0 mL) and the reaction warmed to 50 °C and stirred overnight. The mixture was diluted with water (3 mL) and the product was extracted with EtOAc (2 x 3 mL). The combined organic phases were washed with brine (2 mL), dried over Na 2 SO 4 and filtered.
  • the mixture was diluted with DCM (150 mL), then stirred for 24 h at RT.
  • the suspension was diluted with hexanes and the solid was collected by filtration (66.0 g).
  • the collected solid was suspended in DCM : DIPEA (5:1, 500 mL), stirred for 30 min and then a saturated aqueous solution of NaHCO 3 was added and the mixture stirred for 1 h.
  • the mixture was filtered through Celite®, the layers were separated, and the aqueous layer extracted with DCM (3x).
  • Examples 57 to 61 The compounds in the following table were prepared from (4-(7-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (Example 56, step 6) and the appropriate carboxylic acid, following a similar method to that used for Example 1, step 8.
  • Example 62 5-(2,3-cis-dimethylcyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • Example 63 3-(1-(fluoromethyl)cyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide 1.
  • 6-bromopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate To a solution of 6-bromopyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.47 mmol) in DCM (10 mL) was added TEA (143 mg, 1.41 mmol) and the reaction mixture was cooled to 0 °C in an ice-water cooling bath. Triflic anhydride (265 mg, 0.94 mmol) was added and the reaction stirred at 0 °C for 30 mins.
  • Example 66 Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide
  • 1-(tert-Butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a pink solid (10.7 mg, 45% yield) from (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl) methanamine dihydrochloride (Example 65, step 6) and 1-(tert-butyl)-1H-1,2,3-triazole-4-
  • Example 68 Synthesis of 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • 5-(tert-Butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (7.3 mg, 22% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)phenyl)methanamine dihydrochloride (Example 67, step 3) and lithium 5-(tert-butyl)- 1,2,
  • Example 69 Synthesis of 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide
  • 1-(tert-Butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a white solid (3.5 mg, 10% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl) methanamine dihydrochloride (Example 67, step 3) and 1-(tert-butyl)-1H-1,2,3
  • Example 70 Synthesis of 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide
  • 1-(tert-Butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)benzyl)-1H-pyrazole-3-carboxamide was obtained as a white solid (17.9 mg, 53% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)phenyl)methanamine dihydrochloride (Example 67, step 3) and 1-(tert-butyl)-1H-pyrazole- 3-carboxylic
  • Example 73 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyrazin-8-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 72 step 3, 95.0 mg, 272.34 ⁇ mol
  • lithium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate 96.47 mg, 544.68 ⁇ mol
  • T3P ® 259.96 mg, 817.02
  • Example 74 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyrazin-8-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
  • 1-(tert-Butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8- yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was obtained as an off-white solid (55.7 mg, 62.9% yield) from (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin- 8-yl)piperidin-4-yl)methanamine dihydrochloride (
  • reaction mixture was heated to 100 °C under an atmosphere of N 2 and stirred at that temperature for 1 h.
  • the reaction mixture was cooled to ambient temperature and filtered through Celite®.
  • the filtrate was concentrated and the crude material was purified by silica gel column chromatography (3:1 EtOAc/EtOH:heptanes, from 2% to 100%) to give 5-chloro- 7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine as an off-white solid (84 mg, 75% yield).
  • reaction mixture was stirred at 0 °C for 10 min before (4-(7-(1- methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride (19 mg, 50 ⁇ mol) was added.
  • the reaction mixture was warmed to 23 °C and stirred for 24 h.
  • Water 5 mL was added to quench the reaction, then EtOAc (5 mL) added and the layers were separated.
  • the aqueous phase was extracted EtOAc (2 x 5 mL).
  • the organic phases were combined, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Example 76 N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5- yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-5-(1- methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained (13.8 mg, 48% yield) as a white solid, from potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate and (4- (7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)
  • Example 77 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3- a]pyridin-5-yl)benzyl)-1H-pyrazole-4-carboxamide
  • 1-(tert-Butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5- yl)benzyl)-1H-pyrazole-4-carboxamide was obtained as a white solid (19.6 mg, 68% yield) from 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid and (4-(7-(1-methyl-1H-pyrazol-4-yl)- [1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride (Example 75, step
  • Example 78 5-(tert-butyl)-N-(2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 Example 55, 100 mg, 250.4 ⁇ mol
  • 5- chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine Step 4, Example 56, 58.52 mg, 250.4 ⁇ mol), K 2 CO 3 (103.84 mg, 751.3 ⁇ mol) and Pd(dppf)Cl 2 (9.16 mg, 12.5 ⁇ mol) were dissolved in dioxane
  • Step 1 Example 55, 100 mg, 250.4 ⁇ mol
  • Step 4 Example 56, 58.52 mg, 250.4 ⁇ mol
  • K 2 CO 3 103.84 mg, 751.3 ⁇ mol
  • Pd(dppf)Cl 2 9.16 mg, 1
  • Example 79 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • Preparation of (4-bromo-3-fluoro-2-methylphenyl)methanamine hydrochloride To a solution of 4-bromo-3-fluoro-2-methylbenzonitrile (62.2 g, 290 mmol) in THF (150 mL) was added BH 3 .THF (49.9 g, 581 mmol) and the solution was stirred at 70°C overnight.
  • reaction mixture was heated to 100 °C under an atmosphere of N 2 and stirred at 100 °C for 3 h.
  • the reaction was concentrated and purified via column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:heptane) to afford 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(7-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (88 mg, 99.2% yield) as a light yellow solid.
  • Example 80 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid, 74 mg, 82.1% yield, from 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Step 1, Example 55) and 4-chloro-6-(1-methyl- 1H-
  • Example 81 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • 5-(tert-Butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a light yellow solid, 81 mg, 90.4% yield, from 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Example 79
  • Example 82 5-(tert-butyl)-N-(2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4- oxadiazole-3-carboxamide 1.
  • tert-butyl (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate To a solution of tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (359.1 mg, 0.977 mmol) in dioxane (30 mL) and H 2 O (5 mL) was added 4-chloropyrazolo[1,5-a]pyrazine (150 mg, 0.977 mmol) and K 2 CO 3 (270 mg, 1.95 mmol) at 20 °C.
  • Amine 1 (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 87, step 2)
  • Amine 2 (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 84, step 3)
  • Amine 3 (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 86, step 3)
  • Examples 109 to 114 The compounds in the following table were prepared from (3-fluoro-4-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 83, step 3) and appropriate heterocyclic carboxylic acid, following a similar procedure to that described in Example 108.
  • Example 115 2-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide 1.
  • HATU 46.85 mg, 122.9 ⁇ mol
  • the reaction was concentrated and purified via column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:Heptane) to afford 2-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide (40 mg, 84.5% yield) as a yellow solid.
  • Example 116 5-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide
  • 5-(tert-Butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2- yl)methyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid, 45 mg, 74.3% yield, from (5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2- yl)methanamine hydrochloride and 5-tert-butyl-1,2,4-oxadiazole-3-carbox
  • Example 117 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • DABAL-Me3 47.71 mg, 186.1 ⁇ mol
  • (2-fluoro-4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 6, step 2, 40.0 mg, 124.1 ⁇ mol) and ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (36.90 mg, 186.14 ⁇ mol) in THF (1.24 mL) and the reaction was heated at 45°C overnight.
  • Example 118 3-(tert-butyl)-N-(2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide 1.
  • Example 120 1-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1H-1,2,3-triazole-4-carboxamide 1.
  • HATU 46.17 mg, 121.1 ⁇ mol
  • the reaction was loaded directly onto a silica cartridge and purified by column chromatography (gradient elution 0-100% EtOAc:Heptane) to afford the product as a dark orange film.
  • the material was re-purified by HPLC (Method C3, 10-95%) to give 1-(tert-butyl)-N-(2-methyl-4-(6- morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate (16 mg, 26.4% yield) as a yellow solid.
  • HATU (68 mg, 178.3 ⁇ mol) was added in a single portion and the reaction was stirred overnight at rt. The reaction was diluted with water and passed through a phase separator. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated in vacuo and the residue purified by HPLC (Method C3, 5-50%) afford 1-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1- yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate (52 mg, 54.7% yield).
  • Example 122 1-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2- methylbenzyl)-1H-1,2,3-triazole-4-carboxamide
  • Example 123 2-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-1,2,3-triazole-4-carboxamide DABAL-Me3 (47.56 mg, 185.5 ⁇ mol) was added to a mixture of (2-methyl-4-(6- morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 120, step 3, 49.02 mg, 123.7 ⁇ mol) and ethyl 2-(tert-butyl)-2H-1,2,3-triazole-4-carboxylate (Example 37a, US10377719-B2, 36.6 mg, 185.5 ⁇ mol) in THF (1.24 mL) and the reaction was heated at 45 °C overnight.
  • Example 124 2-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5- a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide trifluoroaceate 2-(tert-Butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-2H-1,2,3-triazole-4-carboxamide trifluoroacetate was obtained, 49 mg, 60.9% yield, from (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 121, step 2) and ethyl 2-(tert-butyl)-2H- 1,2,3-triazole-4-
  • Amine 4 (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 119, step 2)
  • Amine 5 (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Example 120, step 3)
  • Amine 6 (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 118, step 3)
  • Amine 7 (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4- yl)phenyl)methanamine dihydrochloride (Example 121, step 2)
  • Amine 8 (4-(6-(
  • Example 134 N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)- 1,2,4-oxadiazole-3-carboxamide
  • Example 135 5-(tert-butyl)-N-(4-(6-(dimethylamino)pyrazolo[1,5-a]pyrazin-4- yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • DIPEA 89.17 mg, 690 ⁇ mol
  • 1-tert-butyltriazole-4-carboxylic acid 77.82 mg, 460 ⁇ mol
  • HATU 96.45 mg, 253 ⁇ mol
  • Example 144 5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • tert-butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate
  • Examples 145, 146, 147 and 148 N-(((3S,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4- oxadiazole-3-carboxamide, N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4- oxadiazole-3-carboxamide, N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-
  • T3P® (422.7 mg, 664.3 ⁇ mol, 50% purity) was added and the reaction was stirred overnight at rt. Additional equivalents of potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate, DIPEA and T3P® were added and the reaction was stirred overnight at rt. The reaction was diluted with water, extracted with EtOAc (2x), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The material was purified by column chromatography (gradient elution 0-75% [3:1 EtOAc:EtOH]:Heptane) to afford a clear film.
  • Example 152 1-(tert-butyl)-N-((3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 1.
  • T3P® (434.71 mg, 683.1 ⁇ mol, 50% purity) was added and the reaction stirred overnight at rt.
  • the reaction was diluted with water and DCM and passed through a phase separator. The aqueous layer was extracted with DCM and the combined organic layers were concentrated.
  • Example 153 2-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)oxazole-4-carboxamide
  • 2-(tert-Butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)piperidin-4-yl)methyl)oxazole-4-carboxamide was obtained as a white solid, 44 mg, 39.8% yield, from ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)piperidin-4-yl)methanamine (Exa
  • Example 154 N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3- carboxamide
  • Example 155 and 156 5-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N-(((3R,4S)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • HATU (983.60 mg, 2.58 mmol) was added in a single portion and the reaction was stirred overnight at rt.
  • the reaction was concentrated and purified by column chromatography (40 g column, gradient elution 0-100% EtOAc:Heptane) to afford tert-butyl cis-4-((5-(tert- butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-fluoropiperidine-1-carboxylate (405 mg, 49% yield) as a white solid.
  • LCMS m/z 407.2 [M+H] + 2.
  • Example 157 5-(tert-butyl)-N-((3,3-difluoro-1-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • the reaction was diluted with water and DCM and passed through a phase separator. The aqueous layer was extracted with DCM and the combined organic layers were concentrated. The reaction was dissolved in minimal DMSO and purified by reverse phase HPLC (gradient elution 5-70% MeCN:H 2 O w/ 0.1% TFA modifier) and the product was dissolved in MeCN (1 mL) and water (1 mL), and the resulting material was frozen in a dry ice/acetone bath and lyophilized to afford 5-(tert-butyl)-N-((4-fluoro-1-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4- oxadiazole-3-carboxamide trifluoroacetate (47 mg, 38.9% yield,) as a light yellow solid.
  • Example 161 N-((4-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate N-((4-Fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4- yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate was obtained as a light yellow solid, 48 mg, 40.3% yield, from (4-fluoro-1-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-
  • Example 162 1-(tert-butyl)-N-((4-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate
  • Example 164 and 165 5-(tert-butyl)-N-(((1R,5S,8s)-3-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methyl)-1,2,4-oxadiazole- 3-carboxamide and 5-(tert-butyl)-N-(((1R,5S,8r)-3-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methyl)-1,2,4-oxadiazole- 3-carboxamide 1.
  • DIPEA [stereochemistry arbitrarily assigned] DIPEA (638.4 ⁇ L, 3.66 mmol) was added to a mixture of ((1R,5S,8r)-3-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methanamine hydrochloride (300 mg, 731.1 ⁇ mol) and potassium 5-tert-butyl-1,2,4-oxadiazole-3- carboxylate (229.49 mg, 1.10 mmol) in DMF (3.66 mL).
  • T3P® (2.19 mmol, 1.31 mL, 50% purity) was added and the reaction was stirred overnight at rt.
  • the reaction was diluted with water and DCM and passed through a phase separator.
  • the aqueous layer was extracted with DCM and the combined organic layers were concentrated.
  • the crude was purified by column chromatography (gradient elution 0-75% [3:1 EtOAc:EtOH]:Heptane) to afford racemic material.
  • Example 166 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)azepan-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide 1.
  • Example 167 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)azepan-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
  • 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)azepan-4- yl)methyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a yellow solid, 70 mg, 46.7% yield, from (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)azepan-4- yl)methanamine hydrochloride (Example 166, step 3) and 1-tert-butyltriazole-4-
  • Example 169 4-(Cyclobutylmethyl)-1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)piperidin-4-yl)methyl)piperazin-2-one 4-(Cyclobutylmethyl)-1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)piperidin-4-yl)methyl)piperazin-2-one was obtained as a white solid, 44.8 mg, 42.5% yield, from 1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4- yl)methyl)piperazin-2-one hydrochloride (Example 168, step 4) and cyclobutanecarbaldehyde, following a similar method to that described in
  • Example 170 1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin- 4-yl)methyl)-4-propylpiperazin-2-one hydrochloride
  • Example 171 4-methyl-1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)piperidin-4-yl)methyl)piperazin-2-one 4-Methyl-1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4- yl)methyl)piperazin-2-one was obtained as a white solid, 43.7 mg, 52.8% yield, from 1-((1- (6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)piperazin- 2-one hydrochloride (Example 168, step 4) and formaldehyde, following a similar procedure to that described in Example 170.
  • Example 172 1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin- 4-yl)methyl)-4-neopentylpiperazin-2-one
  • 1-((1-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-4- neopentylpiperazin-2-one was obtained as a white solid, 21.2 mg, 22.5% yield, from 1-((1-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)piperazin-2- one hydrochloride (Example 168, step 4) and 2,2-dimethylpropanal, following a similar procedure to that described in Example 170.
  • Example 173 4-isopropyl-1-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- yl)piperidin-4-yl)methyl)piperazin-2-one
  • Btk-PolyGAT-LS Assay The purpose of the BTK in vitro assay is to determine compound potency against BTK through the measurement of IC50. Compound inhibition is measured after monitoring the amount of phosphorylation of a fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitor. The BTK kinase reaction was done in a black 96 well plate (costar 3694).
  • a 24 pL aliquot of a ATP/peptide master mix (final concentration; ATP 10 ⁇ , polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgCl 2 , 200 ⁇ Na3PO4, 5 mM DTT, 0.01% Triton X-100, and 0.2 mg/ml casein) is added to each well.
  • kinase buffer 10 mM Tris-HCl pH 7.5, 10 mM MgCl 2 , 200 ⁇ Na3PO4, 5 mM DTT, 0.01% Triton X-100, and 0.2 mg/ml casein
  • I pL of a 4- fold, 40X compound titration in 100% DMSO solvent is added, followed by adding 15 uL of BTK enzyme mix in 1X kinase buffer (with a final concentration of 0.25 nM).
  • the assay is incubated for 30 minutes before being stopped with 28 pL of a 50 mM EDTA solution. Aliquots (5 uL) of the kinase reaction are transferred to a low volume white 384 well plate (Coming 3674), and 5 pL of a 2X detection buffer (Invitrogen PV3574, with 4 nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate is covered and incubated for 45 minutes at room temperature. Time resolved fluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nm emission; 518 nm fluorescein emission) is measured.
  • TRF Time resolved fluorescence
  • IC50 values are calculated using a four parameter fit with 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control.
  • Table 1 shows the activity of the selected exemplary compounds of this invention in the in vitro Btk kinase assay, wherein each compound number corresponds to the example numbers in Examples 1-173.
  • “ ⁇ ” represents an IC50 of greater than 1 ⁇ M and equal to or less than 10 ⁇ M.
  • ⁇ represents an IC 50 of greater than 10 nM and equal to or less than 1 ⁇ M (10 nM ⁇ IC50 ⁇ 1 ⁇ M ) .
  • “ ⁇ ” represents an IC50 of greater than 1 nM and equal to or less than 10 nM (1 nM ⁇ IC50 ⁇ 10 nM).
  • ⁇ represents an IC50 of less than 1 nM.
  • Table 1 nt not tested In Vitro whole blood CD69 Assay Human heparinized venous blood from health donors was aliquoted into 96-well plate and “spiked” with serial dilutions of formula I compounds in DMSO or with DMSO without drug. The final concentration of DMSO in all wells was 0.1%. The plate was incubated at 37°C for 30 min. Drug-containing samples were stimulated with 0.1 ⁇ g/mL mouse anti- human IgD-dextran (1A62) or 20 ⁇ g/mL polyclonal rabbit F(ab’)2 anti-human IgD.
  • Phosphate-buffered saline PBS was added to the negative control unstimulated sample and the plates were incubated overnight (18 to 22 hours) at 37°C. Cells were stained with fluorochrome-conjugated anti-CD19 and anti-CD69 antibodies. Lyse/fix solution was used to remove red blood cells by hypotonic lysis and to fix the remaining cells, which were then analyzed by flow cytometry. CD19+ B cells were gated and analyzed for CD69 expression. The percentage of B cells expressing CD69 was plotted versus the log10 of the concentration of the drug and the best-fit curves (variable Hill slope) were generated to obtain the IC50 value.
  • Table 2 shows the activity of the selected exemplary compounds of this invention in the in vitro whole blood CD69 assay, wherein each compound number corresponds to the example numbering set forth in the Examples 1-173 herein.
  • ⁇ represents an IC 50 of greater than 10 ⁇ M.
  • ⁇ represents an IC 50 of greater than 1 ⁇ M and equal to or less than 10 ⁇ M (1 ⁇ M ⁇ IC50 ⁇ 10 ⁇ M ).
  • ⁇ represents an IC50 of less than 1 ⁇ M.

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Abstract

L'invention concerne des composés de formule (I) : ou des sels pharmaceutiquement acceptables de ceux-ci, les variables dans la formule (I) étant telles que définies dans la description ; et des méthodes pour leur utilisation et leur production.
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WO2013063549A1 (fr) * 2011-10-28 2013-05-02 Vanderbilt University Analogues substitues 2-(4-heterocyclylbenzyle)isoindoline-1-un employes comme modulateurs allosteriques positifs du recepteur m1 acetylcholine muscarinique
WO2014064131A2 (fr) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
WO2015089327A1 (fr) 2013-12-11 2015-06-18 Biogen Idec Ma Inc. Composés biaryliques utiles pour le traitement de maladies humaines en oncologie, neurologie et immunologie
WO2017087837A1 (fr) * 2015-11-20 2017-05-26 Forma Therapeutics, Inc. Purinones utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 1
WO2018191577A1 (fr) 2017-04-14 2018-10-18 Biogen Ma Inc. Analogues de benzoazépine utilisés en tant qu'agents inhibiteurs de la tyrosine kinase de bruton
US10377719B2 (en) 2015-11-26 2019-08-13 Hoffmann-La Roche Inc. Trypanosomes inhibitors
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WO2013063549A1 (fr) * 2011-10-28 2013-05-02 Vanderbilt University Analogues substitues 2-(4-heterocyclylbenzyle)isoindoline-1-un employes comme modulateurs allosteriques positifs du recepteur m1 acetylcholine muscarinique
WO2014064131A2 (fr) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
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WO2017087837A1 (fr) * 2015-11-20 2017-05-26 Forma Therapeutics, Inc. Purinones utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 1
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